Process for making amlodipine, derivatives thereof, and precursors therefor

ABSTRACT

Purification of the phthalimidoamlodipine intermediate, especially by recrystallization, can provide an easier route to obtaining pharmaceutically pure amlodipine or its salts.

This application is a Divisional of application Ser. No. 11/060,887,filed Feb. 19, 2005, which is a Divisional of application Ser. No.10/431,536, filed May 8, 2003, now U.S. Pat. No. 6,858,738, which is aDivisional of application Ser. No. 09/938,840, filed Aug. 27, 2001, nowU.S. Pat. No. 6,653,481, which is a Continuation-in-Part of applicationSer. No. 09/809,351, filed Mar. 16, 2001, the entire contents of eachapplication being incorporated herein by reference. Further, applicationSer. Nos. 09/938,840 and 09/809,351 each claim the benefit of U.S.Provisional Application 60/258,613, filed Dec. 29, 2000.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to novel intermediates useful in thesynthesis of amlodipine and related compounds as well as to processes ofmaking and using the same.

2. Description of the Related Arts

EP 89167 and corresponding U.S. Pat. No. 4,572,909 describe a class ofdihydropyridine derivatives that exhibit antianginal andantihypertensive properties. One of the compounds disclosed therein hasbecome a commercially important compound that is now known asamlodipine: or2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylicacid 3-ethyl 5-methyl ester, having the following formula:

This compound, in the form of its besylate salt as described in EP 244944 and in corresponding U.S. Pat. No. 4,879,303, is the activeingredient in the prescription pharmaceutical composition NORVASC soldby Pfizer Pharmaceuticals for management of hypertension and anginapectoris.

Generally, the synthetic route disclosed in EP 89167 for makingamlodipine and the other related dihydropyridine compounds comprisesforming the corresponding amino-group protected precursor followed bydeprotection. Suitable protecting groups for the amino side chain groupinclude benzylamino, dibenzylamino, azido and phthalimido groups. One ofthe precursors for amlodipine uses a phthalimido protecting group and isrepresented by the following formula (2a).

This compound, which is hereinafter referred to as“phthalimidoamlodipine,” has certain advantages among otheramino-protected precursors for amlodipine as it may be easily separatedfrom the reaction mixture without danger (e.g. the azido-amlodipine isexplosive) and is converted to amlodipine by simple, common deprotectionprocedures, e.g. by reaction with methylamine, hydrazine etc. It is thusconsidered to be a particularly useful key intermediate for industrialproduction of amlodipine.

J. Med. Chem. 1986, 29, 1696-1702 discloses two routes for making thephthalimidoamlodipine and other related amino-protected precursors. Thefirst route comprises reacting a substituted benzaldehyde (A), such as2-chlorobenzaldehyde, with methyl 3-aminocrotonate (B 1) and aminoprotected aminoethoxy-methylacetoacetate (C1′).

The compound (C1′) is prepared by a condensation of ethyl2-chloroacetoacetate (shown hereinafter as compound (F)) with anappropriately substituted sodium alkoxide. Where —N(prot) represents aphthalimido-group, the alkoxide can be N-(2-hydroxyethyl)phthalimide(shown hereinafter as compound G).

The second route disclosed in this article, comprises reacting abenzylidene derivative (D1) (prepared in an extra step by an addition ofa compound of formula (A), such as o-chlorobenzaldehyde, to methylacetoacetate) with a substituted aminocrotonate (E1) (prepared in situfrom the above amino-protected aminoethoxymethylacetoacetate (C1′) andammonium acetate).

This variant was also applied to the synthesis of phthalimidoamlodipine(2a) in WO 00-24714. Therein, the intermediating phthalimido-substitutedaminocrotonate (E1) was not prepared in situ but was prepared andisolated in a solid state in an extra step prior to the reaction withthe benzylidene compound.

The above methods suffer from yield and/or purity inefficiencies due tothe reactivity of starting materials leading to formation of sideproducts. For example, phthalimidoamlodipine is reported in theabove-mentioned J. Med. Chem. Article as being prepared in 25% yield byfollowing the first scheme (see compound 41 in Table I on page 1698). Itwould be desirable to provide a process for making phthalimidoamlodipineand related compounds in good yield and with good purity.

SUMMARY OF THE INVENTION

It has now been discovered that phthalimidoamlodipine (2a) as well asrelated phthalimido-protected precursors can be prepared by a convenientmethod, with a good yield and purity, by employing a new startingmaterial. Accordingly, a first aspect of the invention relates to acompound having the formula (3):

wherein R₂ represents a C₁-C₄ alkyl group, preferably an ethyl group.The compounds of formula (3) can be reacted with an alkyl3-aminocrotonate of formula (B) to form a phthalimido-protectedprecursor of formula (2) as shown below:

wherein R₁ and R₂ each independently represent a C₁-C₄ alkyl group. Thecompounds of formula (2) can be deprotected to form compounds of formula(1):

Preferably R₁ is methyl and R₂ is ethyl whereby the process formsamlodipine via the phthalimidoamlodipine (2a). The other compounds offormula (1) are also useful as calcium channel blockers for treatingangina or hypertension. Additionally, these compounds and thecorresponding phthalimido-protected precursors of formula (2) are usefulas reference standards or markers for checking the respective purity ofamlodipine or phthalimidoamlodipine, a salt thereof, or a compositioncontaining the same; i.e. assaying for these formula (1) compounds whichcan be formed as side-products in commercial manufacture of amlodipinevia transesterification for example.

DETAILED DESCRIPTION OF THE INVENTION

The present invention deals with new compounds, alkyl2-(o-chlorobenzylidene)-4-(2-phthalimidoethoxy)acetoacetates of formula(3)

wherein R₂ represents a C₁-C₄ alkyl group and it preferably representsan ethyl group (compound 3a), a methyl group (compound 3b) or anisopropyl group (compound 3c).

The compound (3) may be prepared in a sufficiently pure state and simplyisolated from a crude reaction mixture by any conventional techniques.Such an isolated form of the compound (3) can be further purified ifneeded or used directly in the next synthetic step. Due to the presenceof a carbon-carbon double bond in the molecule, the compound (3) may beprepared as a mixture of cis- and trans-isomers or as a single cis- ortrans isomer. The formation of a trans-isomer is driventhermodynamically (trans-isomer is preferably formed at elevatedtemperatures), while the formation of cis-isomer is driven kinetically.From the use aspects, the compound (3) in a form of a mixture of cis-and trans isomers is preferred; however, single isomers are also withinthe scope of the invention.

Among the compounds of general formula (3), the compound (3a) isparticularly important as it represents an industrially applicableintermediate in the synthesis of amlodipine.

The present invention also provides a process for providing the compoundof formula (3), comprising reacting o-chlorobenzaldehyde with alkyl4-(2-(phthalimido)ethoxy)acetoacetate of formula (C).

Typically the reaction is carried out in a reaction solvent, preferablyan organic solvent such as an alcohol, especially isopropanol or in ahydrocarbon such as benzene, advantageously in a presence of an organicbase such as piperidine or piperidine acetate. The solvent should be onein which the compound (3) product is only sparingly soluble, so that itmay be separated from the rest of the unreacted starting materials andalso from any potential side products. The reaction may be performed attemperatures from close to ambient up to the boiling point of thesolvent, usually about 20 to 55° C., preferably at 20-40° C. Waterformed by the reaction may be separated out e.g. by azeotropicdistillation though this is not required.

If the reaction is performed in isopropanol, the product (3) separatesout in an oily state. Preferably the compound (3) oil is recovered andused directly without further purification to form phthalimidoamlodipineas such oil contains only minor amounts of impurities and the remainingstarting materials can be easily removed. Recovery can be by any knowntechnique and is typically accomplished by a liquid-liquid phaseseparation optionally with washing of the oil product. It should beunderstood that such washing is not intended to be considered a“purification step”, but rather merely part of the recovery. Thus, it isan advantage of this process that although the disadvantages of an“in-situ” production of (3) are avoided, the isolation and purificationof the intermediate (3) is not necessary.

In a preferred embodiment, the process provides the compound (3a) asoutlined below.

The usual ratio of cis- and trans isomers of the compound (3) formed inthe process of our invention is from about 7:3 to about 5:5,respectively. For example, compounds (3a) and (3c) are usually formed ina cis:trans ratio of about 6:4 while the compound (3b) is usually formedat about a 1:1 ratio of cis:trans.

Another possibility for preparing the compounds of formula (3) could beby reacting o-chlorobenzaldehyde with an alkyl2-chloroacetylacetoacetate (F), such as ethyl 2-chloroacetylacetoacetate(F 1), under general conditions described in EP 212340, to form abenzylidene-2-chloroacetylacetoacetate intermediate of formula (4). Thecompound (4) is reacted with N-(2-hydroxyethyl)phthalimide (G) to formthe compound (3). The process is outlined in the following scheme withregard to forming compound (3a).

All of the starting materials for the above-described reaction schemes,e.g. compounds of formula (C), (F), etc., are either commerciallyavailable or readily obtained by workers of ordinary skill by methodssufficiently described in the prior art.

The compounds of formula (3) can be used to produce aphthalimido-protected precursor of formula (2) by reacting the same withan alkyl 3-aminocrotonate of formula (B) as shown below.

R₁ and R₂ each independently represent a C₁-C₄ alkyl group. The reactionbetween (3) and (B) may preferably be performed in a suitable solvent,e.g. in isopropanol, at elevated temperatures, advantageously at 70-90°C., as the reaction is thermally driven. The speed of reaction may beenhanced by the addition of a catalytic amount of a strong acid and/orby addition of a dehydrating agent, e.g., a molecular sieve, fortrapping the formed water. After the reaction, the product (2) may beisolated in a solid state after cooling the reaction mixture and/orafter concentration of the reaction mixture. If desired, the product (2)can be purified by recrystallization from a solvent such as methanol,ethanol, 2-propanol, ethyl acetate, etc. or a mixture of two or more ofsuch solvents. After a single recrystallization, e.g. from ethylacetate, the product typically exhibits a purity higher than 98%.

Thus, in summary, the use of the compound (3) of our invention in thesynthesis of phthalimidoamlodipine (2a) and other relatedphthalimido-protected precursors avoids the disadvantages of bothdisclosed synthetic variants of the prior art. In respect to the variant1, it allows for a reduction in side products by producing a stableintermediate that is easily separable from the rest of the reactivestarting materials, thereby reducing the chance of side effects insubsequent reaction steps. In respect to variant 2, it does not requirean extra step of conversion of a keto group to an amino group whichdecreases the overall yield of the process and further it does notrequire an isolation of the intermediate in a crystalline state.Further, the fact that the chlorobenzaldehyde is reacted in a separatestep so that the unreacted portion may be absent from the finalcyclization reaction is advantageous in both the yield and purity of thecompounds of formula (2).

The compounds of formula (2) can be subjected to a deprotecting step toform a compound of formula (1).

Again R₁ and R₂ each independently represent a C₁-C₄ alkyl group.Phthalimidoamlodipine and other compounds of formula (2) may beconverted to amlodipine and corresponding analogues as represented byformula (1) by any of the conventional methods of deprotection of thephthalimido group such as those disclosed in EP 89167. Examples ofdeprotecting agents include ethanolic methylamine, hydrazine hydrate oralkali metal hydroxide/acid treatment. Particularly preferred however isa variant of the first method that employs commercially availableaqueous solution of methylamine. The reaction with aqueous methylaminemay be performed at a temperature from the ambient to approx. 60° C.,preferably at 25-40° C. In a preferred embodiment, amlodipine free baseis subsequently separated out from the concurrently producedmethylphthalimide by an extraction of the aqueous reaction mixture witha water immiscible organic solvent, e.g. by toluene, and, optionally, isisolated from the solution in that solvent.

Amlodipine as well as all the compounds of formula (1) may be isolatedas a free base and/or it may be converted into an acid addition salt bya reaction of the base with the corresponding acid. Alternatively, acidaddition salts of amlodipine and of other compounds of formula (1) maybe prepared without isolating the corresponding free base. For instance,a solution of amlodipine free base obtained from the step ofdeprotection of phthalimidoamlodipine may be used as well. The solutionof crude base, without need of isolation of such free base, is contactedwith corresponding acid, and the formed salt is separated from thesolution.

Suitable acid addition salts include pharmaceutically acceptable acidaddition salts of amlodipine such as amlodipine besylate, hydrochloride,fumarate, maleate and mesylate, including solvates and hydrates thereof.Particularly suitable are amlodipine maleate and amlodipine mesylatemonohydrate.

The compounds of formula (1) can be formulated into a pharmaceuticalcomposition comprising an effective amount of amlodipine or apharmaceutically acceptable salt thereof and at least onepharmaceutically acceptable excipient. Generally the pharmaceuticalcomposition is in the form of a unit dose having from 1 to 25 mg of thecompound of formula (1), measured as the free base. This usuallyprovides a dose sufficient to treat or prevent angina or hypertension.Suitable dosage forms include oral solid dosage forms such as tabletsand capsules or liquid forms such as for oral or parenteraladministration. The compositions can be made by known techniques such aswet or dry granulation techniques including direct compressiontabletting.

Additionally, the compounds of formula (1) can also be used as referencestandards or markers for checking the purity of amlodipine. Particularlyuseful are the analogues of amlodipine of the formulae (1b), (1c), (1d),(1e) and (1f).

The compounds (1b)-(1f) are important side products/impurities which mayappear in the industrial production of amlodipine, especially when analcohol solvent is employed. That is, the compounds of formula (2) andformula (1) can undergo transesterification such that R₁ or R₂ or bothare changed from one alkyl group to another. Thus, the followingcompounds (2b)-(2f) may also arise during the production of amlodipinefrom the phthalimidoamlodipine precursor and are also useful as markersor reference standards for monitoring purity.

When present as an unintended transesterification impurity/side-product,the compounds (2b)-(2f) will also convert into their correspondingcompound (1b)-(1f) during the deprotection step. Alternatively, duringthe deprotection step or any later processing step, the compounds offormula (1) can also undergo transesterification thereby changing thealkyl group in one or both of the R₁ and R₂ positions.Transesterification can occur unintentionally during the production ofamlodipine, either by the present process or the prior methods, where analcohol solvent such as ethanol, isopropanol, etc. is used.Transesterification reactions may appear in whatever production step inthe production of phthalimidoamlodipine, so that a producer shouldappreciate to have a method by which the amounts of such undesiredproducts could be monitored.

Fortunately, the process of the present invention allows for theformation of the compounds (1b)-(1f) and (2b)-(2f) in a sufficientlypure state so as to be suitable for use as a reference standard ormarker in detecting the presence of these potential impurities in theamlodipine, its salts, its precursors, and its compositions includingpharmaceutical compositions, and in the phthalimidoamlodipine, itssalts, and its compositions, respectively.

In detail, compounds (2b)-(2f) are preparable in an essentially purestate by following the process of the invention as described above.Alternatively, the compounds of formula (2) may be subjected to a(deliberate) transesterification reaction to provide other compounds ofthe same general formula (2), however bearing other groups R₁, R₂. Anexample of this process is set forth hereinafter for the synthesis of(2e).

To obtain the compound (2b), the compound (3a) of our invention reactswith ethyl 3-aminocrotonate (compound (B2)). To obtain the compound(2c), the compound (3b) reacts with methyl 3-amino crotonate (B1) toyield the desired product (2c). The compound (3b) can be prepared, interalia, by condensation of o-chlorobenzaldehyde with methyl4-(2-(phthalimido)ethoxy)acetoacetate (compound C2). Compound C2 can beprepared by a prior art procedure as described above for compound C1′.

To obtain the compound (2d), compound (3b) reacts with ethyl3-aminocrotonate (B2) in analogy with the above.

Synthesis of the compound (2f) starts from the isopropyl-analogue ofcompound (3a), i.e. from compound (3c). The compound (3c) can beprepared by both the processes of the present invention outlined above,advantageously by condensation of o-chlorobenzaldehyde with isopropyl4-(2-(phthalimido)ethoxy)acetoacetate (compound C3). Compound C3 can beprepared by a prior art procedure as described above for compound C1′.The prepared compound (3c) reacts with methyl 3-amino crotonate (B1) toyield the desired product (2f) under basically same conditions asoutlined above.

To obtain the compound (2e), phthalimidoamlodipine (2a) istransesterified by heating in isopropanol under catalysis of a strongacid, e.g. sulfuric acid.

Amlodipine analogues (1b)-(1f) may be obtained from correspondingphthalimidoamlodipine analogues (2b)-(2f) under reaction conditions asknown and/or as described above for the synthesis of amlodipine.Accordingly, compounds (1b)-(1f) may be purified to a desired degree ofpurity by conventional purification methods and/or may be converted intoconventional acid addition salts and optionally purified. Alternatively,the compounds (1b)-(1f) can be prepared by subjecting amlodipine to a(deliberate) transesterification reaction.

The process of testing of purity of products comprising amlodipine(“amlodipine products”) or phthalimidoamlodipine advantageouslycomprises, in essence, any technique that can resolve or otherwisedetect the presence of the target compound. Examples of this type ofassay include thin layer chromatography (TLC) and high performanceliquid chromatography (HPLC).

The amlodipine product to be assayed for the presence of any one or moreof potential amlodipine impurities (1b)-(1f) is any product thatcomprises amlodipine free base or any acid addition salt of amlodipine.Examples of the amlodipine product include the reaction mixture obtainedafter deprotection of phthalimidoamlodipine, crude amlodipine free baserecovered during synthesis, purified amlodipine free base, reactionmixture obtained in the production of acid addition salts of amlodipine,crude acid addition salt of amlodipine or purified acid addition salt ofamlodipine of any suitable form including crystalline forms or amorphousforms, and pharmaceutical unit dosage forms containing the same. Acidaddition salt of amlodipine means any acid addition salt, however saltswith pharmaceutically acceptable acids are preferred; examples of suchsalts are amlodipine besylate, amlodipine maleate, amlodipine fumarate,amlodipine hydrochloride, amlodipine mesylate, etc. Typically suchamlodipine products are made in batches or lots for production purposes.A production lot should be checked to insure that the level of any ofamlodipine analogue (1b)-(1f) is within specification; i.e., a qualitycontrol test to insure that the amlodipine impurities (1b)-(1f) arebelow a predetermined limit. A sample from the production lot is takenand assayed for the presence of amlodipine analogue and preferably alsofor the content of amlodipine. Typically the production lot must containless than 1.0 wt %, preferably less than 0.5%, more preferably less than0.2% and most preferably less than 0.1% of any of the compounds(1b)-(1f) based on the amount of amlodipine or amlodipine salt.Generally the entire production lot, minus any retained sample(s), willbe released by the manufacturer unless an unacceptable level ofamlodipine impurity is found. In that case, the production lot will notbe sold or released; i.e. neither placed in commerce nor used inproduction of final forms.

The amlodipine analogue (1b)-(1f) is assayed under a set of conditionsto produce a reference standard analytical result. A “reference standardanalytical result” may be a quantitative or qualitative result and canbe in any form including numerical, graphical, pictorial, etc. In somecases the result can be stored electronically for later comparisons.

Assaying of the amlodipine product results in an analytical result forthe sample. Typically the sample analytical result is compared in somefashion to the reference standard analytical result for correspondingamlodipine analogue. The comparison can be done manually such as byvisual observation and/or by an automated procedure. The referencestandard analytical results can be obtained essentially concurrentlywith the sample analytical results such as immediately before, during orimmediately after the assaying of the amlodipine product sample, or theycan be obtained earlier, even months or years earlier. In someembodiments the reference standard analytical results are electronicallystored and used by a computer algorithm to determine the presence of theamlodipine analogue and its amount. This latter embodiment includescalibrating the equipment based on the reference standard analyticalresults or results derived therefrom and/or providing a so-calledinternal normalization. All such comparisons, whether direct, indirect,manual or automated, are included within the meaning of “comparing.”

The assay used in determining the reference standard analytical resultsis generally also the same assay with the same set of conditions used totest the amlodipine product, although such is not necessarily required.

The invention will be further described with reference to the twopreferred assay techniques, namely TLC and HPLC. In TLC, samples of thetested amlodipine product, and reference standards of amlodipineanalogues are chromatographed on a suitable chromatographic plate by asuitable developing liquid (mobile phase) under set conditions. Theseconditions include the solvent, the concentration of the sample in thesolvent and the amount of solution applied to the plate. Selectingappropriate solvents and concentrations is well known within the art.The analytical results produced under these conditions may include theRf value, namely the ratio of distance traveled by the correspondingmaterial to the distance traveled by the solvent, and/or the size of thespot produced on the chromatogram.

Preferably, the reference standard is applied at the same time and tothe same chromatographic plate as the tested sample thereby allowing forside-by-side comparisons. In other embodiments the reference standard isalready defined and is simply compared with the developed samplechromatogram. Amlodipine analogues may also be premixed in definedratios to form a mixed reference standard.

Thus one process for testing the purity of a sample comprisingamlodipine comprises the steps of:

a) dissolving a sample comprising amlodipine in a solvent to produce asample solution

b) dissolving a sample of any or more of amlodipine analogues 1b)-1f) ina solvent to produce a reference solution

c) subjecting the sample solution and the reference solution to thinlayer chromatography to obtain a TLC chromatogram for each and

d) estimating the intensity of any secondary spot obtained from thesample solution which corresponds in R_(f) value to the referencemarker, against the intensity of the spot due to the correspondingamlodipine analogue in the chromatogram of the reference solution.

Similarly an assay using HPLC can also be formulated. The referencestandard analytical results may include the resolution factor, responsefactor, the retention time, and/or the peak area. For example, a processfor testing the of a sample comprising amlodipine comprises the stepsof:

a) dissolving a sample comprising amlodipine in a solvent to produce oneor more sample solutions;

b) dissolving a sample of any or more of amlodipine analogues (1b)-(1f)in a solvent to produce a reference solution;

c) injecting the sample and reference solutions to an HPLC column; and

d) estimating the peak areas of each solution and calculating from thesethe content of the or any of the amlodipine analogue(s) (1b)-(1f) ineach sample solution.

In this embodiment, it may be necessary or desirable to run a systemsuitability solution through the HPLC column prior to step c) in orderto determine the resolution factor between amlodipine and any othercompound present in the sample. In that case the method includes theadditional step of

b′) dissolving amlodipine and a suitable external standard(s) to producea system suitability solution, and injecting the system suitabilitysolution onto the HPLC column to determine resolution factor(s).

As an alternative to assaying a sample of the reference markerseparately each time, a parameter known as the Response factor (R) maybe used. The response factor is a previously determined ratio of anumerical result (e.g. peak area at HPLC) obtained by testing a sampleof the aspartate or the maleamide, by a given analytical technique, tothe corresponding numerical result obtained by testing the same amountof pure amlodipine maleate at an equivalent concentration. The knownresponse factor for amlodipine aspartate or amlodipine maleamide can beused to calculate the amount of that particular marker in the testsample. In this way, the relative amount of the impurity to theamlodipine maleate in the sample can be determined as is well known inthe art.

The principles and techniques of testing of purity of amlodipineproducts disclosed above may be, mutatis mutandis, applied also fortesting of purity of corresponding phthalimido-protected precursorproducts of formula (2) (e.g., raw, purified, reaction mixturescomprising the same, salts thereof, etc), using compounds (2a)-(2f) asreference markers. The testing of phthalimidoamlodipine products for thepresence and amount of phthalimidoamlodipine impurities (2b)-(2f) isimportant as, knowing the corresponding result, a producer may properlydecide whether and how the phthalimidoamlodipine product may be purifiedor otherwise reprocessed before its conversion to amlodipine and,accordingly, whether or how the conditions in production ofphthalimidoamlodipine should be adjusted to obtain a product withimproved quality. Phthalimidoamlodipine having the content of any ofanalogues (2b)-(2f) below a predetermined limit may yield amlodipineessentially free of the corresponding amlodipine impurities (1b)-(1f) sothat the amlodipine is not required to be further purified; thus savingtime and energy and improving the overall economy of the amlodipineproduction. Typically the impurity level should be less than 1 wt %,preferably less than 0.5 wt %, more preferably less than 0.2 wt % andeven less than 0.1 wt %.

In one embodiment, a batch of phthalimidoamlodipine is tested for purityby removing a sample therefrom and assaying for one or more of thepotential phthalimidoamlodipine impurities (2b)-(2f). The presence andamount of impurity are determined by comparison to a known referencestandard analytical result for the impurity such as by HPLC or TLC asdescribed above. If the sample is determined to contain the impuritybelow a predetermined level, then the phthalimidoamlodipine batch issubjected to a deprotection step to form a batch of amlodipine. If thesample is determined to contain an amount of the impurity above thepredetermined level, then the phthalimidoamlodipine batch can bere-processed or purified such as by crystallization in order to reducethe impurity level below the predetermined limit, or it may bediscarded. In this way, amlodipine product is not produced when theproduct will inevitably have too much amlodipine impurity. Not only cansuch a process improve efficiency and cut waste but also, in somecircumstances, it may be easier to separate the phthalimidoamlodipineimpurities from phthalimidoamlodipine than it is to separate theamlodipine impurities from amlodipine; thereby improving the overallyield. The batch of phthalimidoamlodipine from which a sample is takencan be either the crude or isolated phthalimidoamlodipine product or itcan be a purified product. For example, a purified product can beobtained by (re)crystallizing the isolated product one or more times asdescribed above. Other purification techniques can also be used, ifdesired. Generally the level of phthalimidoamlodipine impurity is set to1.0 wt % or less, more typically 0.5 wt % or less, and even less than0.1 wt %. Once the phthalimidoamlodipine batch is determined to containthe less than the predetermined amount of impurity, the batch issubjected to deprotection and converted to a batch of amlodipine. Theamlodipine is generally converted to a pharmaceutically acceptable saltthereof and then combined with at least one pharmaceutically acceptableexcipient to form a pharmaceutical unit dosage form such as a tablet ora capsule. These unit dosage forms contain an effective amount ofamlodipine. Preferably, the amlodipine batch, or the amlodipine salt, orthe amlodipine unit dosage form, or a combination thereof are subjectedto an assay for the level of at least one amlodipine impurity of(1b)-(1f). If the level of amlodipine impurity is above a predeterminedlevel, then the amlodipine product may be re-processed or otherwise notreleased or sold.

The following Examples illustrate the invention.

EXAMPLE 1Ethyl-(o-chlorobenzylidene)-4-(2-phthalimidoethoxy)acetoacetate(compound 3a)

300 g of ethyl 4-(2-(phthalimido)ethoxy)acetoacetate was mixed with 90ml of 2-chlorobenzaldehyde and 140 ml of 2-propanol. The solution wasagitated at 20-25° C. and the solution of 3.6 ml of piperidine in 40 mlof 2-propanol was added dropwise during 2 hours. The mixture was thanstirred for 1 hour at the same temperature and 2 hours at 35-40° C. Themixture was acidified with 4.1 ml of acetic acid, 500 ml of 2-propanolwas added and the solution was cooled to 0-5° C. Two layers are formedin the reaction mixture; the upper one was separated and the lowerorganic layer was again washed with 200 ml of 2-propanol. The organiclayer, containing the desired product, was evaporated to dryness inorder to remove the residual solvent.

Yield: 350 g (84%), as the mixture of cis and trans isomers (6:4).Content of 2-chlorobenzaldehyde less than 5%.

EXAMPLE 1A Ethyl2-(o-chlorobenzylidene)-4-(2-phthalimidoethoxy)acetoacetate (compound3a)

-   -   4.2 g of ethyl 4-(2-(phthalimido)ethoxy)acetoacetate was        dissolved in    -   4 ml of isopropanol, under N₂, at room temperature.    -   1.9 g of 2-chlorobenzaldehyde was added thereto.    -   0.075 g of piperidine in    -   1 ml of IPA was added slowly in 2 hours. When addition was        complete the mixture was heated to 35°-40° C. for 2 hours.    -   0.8 g of acetic acid glacial in    -   4 ml of IPA was added and the mixture was cooled to 3°-5° C. in        the refrigerator. The solvent was decanted and the gum like        solid washed with    -   2×5 ml of IPA.

For analytical purposes, a portion of the raw product was purified by achromatography on silica gel 60 using a 1:1 (v/v) mixture of ethylacetate and n-heptane as the eluent. After collection of the fractioncontaining the product, the solvent was evaporated leaving an oil.

NMR shows a mixture of Z and E-isomers, whereby the Z/E ratio isapproximately 6:4.¹H-NMR Spectrum:

The ¹H-NMR spectrum was measured at 303.2 K on a Bruker Avance-400 indeuterated chloroform at 400 MHz. δ Assignment 1.12 (t, ˜1.2H,J_(1,2)=7.2Hz, H-1_((E))); 1.32 (t, ˜1.7H, J_(1,2)=7.2Hz, H-1_((Z)));3.70 (t, ˜1.2H, J_(14,15)=5.6Hz, H-14_((E))); 3.81 (t, ˜0.8H,J_(14,15)=5.6Hz, H-14_((Z))); 3.86 (t, ˜1.2H, J_(14,15)=5.6Hz,H-15_((E))); 3.94 (t, ˜0.8H, J_(14,15)=5.6Hz, H-15_((Z))); 4.17 (s,H-13_((E))); 4.18 (q, J_(1,2)=7.2Hz, H-2_((Z))) (+4.17 sum 2H); 4.27 (q,˜1.2H, J_(1,2)=7.2Hz, H-2_((E))); 4.48 (s, ˜0.7H, H-13_((Z))); 7.26 (bm,3H, H-9_((E+Z))+H-10_((E+Z))+H-11_((E+Z))); 7.40 (bd, 1H, H-8_((E+Z)));7.70 (m, ˜2H, H-19_((E+Z))+H-20_((E+Z))); 7.81 (m, 2H,H-18_((E+Z))+H-21_((E+Z))); 7.92 (s, H-5_((Z))); 7.94 (s,H-5_((E))(+7.92 sum ˜1H).¹³C-NMR Spectrum:

The ¹³C-NMR spectrum was measured at 303.2 K on a Bruker Avance-400 indeuterated chloroform at 100.6 MHz. δ Assignment  13.65 (C-1_((Z))); 14.04 (C-1_((E)));  37.13 (C-15_((E)));  37.19 (C-15_((Z)));  61.53(C-2_((Z)));  61.71 (C-2_((E)));  68.21 (C-14_((Z)));  68.39(C-14_((E)));  74.20 (C-13_((Z)));  75.69 (C-13_((E))); 123.13(C-18_((E))+C-21_((E))); 123.17 (C-18_((Z))+C-21_((Z))); 126.52(C-11_((Z))); 127.02 (C-11_((E))); 129.56 (C-8_((Z))); 129.65(C-10_((Z))); 129.81 (C-8_((E))); 130.13 (C-10_((E))); 131.09(C-9_((Z))); 131.20 (C-9_((E))); 131.57 (C-6_((E))); 132.08(C-17_((E+Z))+C-22_((E+Z))); 132.29 (C-6_((Z))); 133.64 (C-4_((Z)));unknown (C-4_((E))); 133.81 (C-19_((Z))+C-20_((Z))); 133.83(C-19_((E))+C-20_((E))); 134.50 (C7_((E))); 134.60 (C-7_((Z))); 139.93(C-5_((E))); 140.18 (C-5_((Z))); 163.65 (C-3_((E))); 165.95 (C-3_((Z)));168.04 (C-16_((E))+C-23_((E))); 168.09 (C-16_((Z))+C-23_((Z))); 194.15(C-12_((Z))); 201.53 (C-12_((E))).

EXAMPLE 2 3-Ethyl 5-methyl4-(2-chlorophenyl)-2-{[2-(1.3-dioxo-1.3-dihydro-2H-isoindol-2-yl)ethoxy]methyl}-6-methyl-1.4-dihydro-3.5-pyridinedicarboxylate (=phthalimidoamlodipine, compound 2a)

350 g of crude ethyl 2-(o-chlorobenzylidene)-4-(2-phthalimidoethoxy)acetoacetate from Example 1 was dissolved in 540 ml of 2-propanol at 80°C. 50 g of methyl-3-aminocrotonate was added and the mixture was heatedat the same temperature for 16 hours. The mixture was evaporated todryness. The residue was dissolved in 540 ml of glacial acetic acid at80° C. The mixture was cooled to 15° C. and stirred at the sametemperature for 20 hours. The formed solid was filtered off and washedwith 280 ml of glacial acetic acid. The solid was suspended in 225 ml ofmethanol and agitated for 30 minutes. The solid was filtered off, washedwith 75 ml of methanol and dried.

Yield: 229.5 g (56%) of crude product, purity (HPLC)-98% The product wasrecrystallized from ethyl acetate

Yield of the crystallisation: 90%, purity (HPLC)-99%.

EXAMPLE 3 Preparation of Amlodipine Maleate

Into a glass vessel, 80 ml of 40% aqueous methylamine and 8.0 g of theproduct from Example 2 were charged under stirring. The suspension wasagitated at 25° C. for 24 hours. To the mixture, 120 ml of toluene wasadded and the mixture was agitated for 30 minutes. Then the agitationwas stopped for separation of layers. The water layer was separated anddischarged. The toluene layer was washed with 40 ml of water and toluenewas evaporated at max. 60° C. on a rotary vacuum evaporator, until thefirst precipitate occurred. 4 ml of EtOH was added and after dissolving,the solution was filtered.

A solution of 1.74 g of maleic acid in 20 ml of EtOH was added to theethanolic solution. After about 10 minutes of agitation, the solutionstarted to crystallise. The mixture was cooled to 5-10° C. and agitatedat the same temperature for 1 hour. The precipitate was filtered andwashed with 2×6 ml of EtOH.

The product was dried at max 40° C. for 24 hours.

Yield: 5.84 g of amlodipine maleate.

EXAMPLE 4 Methyl2-(o-chlorobenzylidene)-4-(2-phthalimidoethoxy)acetoacetate (Compound3b)

85 g of methyl 4-(2-(phthalimido)ethoxy)acetoacetate was agitated with31.7 ml of 2-chlorobenzaldehyde and 37 ml of 2-propanol at 20-25° C. Thesolution of 1.1 ml of piperidine in 14 ml of 2-propanol was addeddropwise during 1.5 hour. The mixture was than agitated for 2 hours atthe same temperature and for 2 hours at 35-40° C. The mixture wasacidified with 1.5 ml of acetic acid, 140 ml of 2-propanol was added andthe solution was cooled to 0-5° C. The isopropanolic layer was separatedand the organic layer was again washed with 53 ml of 2-propanol. Theorganic layer, containing the desired product, was evaporated to drynessin order to remove the residual solvent.

Yield: 104 g (87%), as the mixture of cis and trans isomers.

EXAMPLE 5 Dimethyl4-(2-chlorophenyl)-2-{[2-(1.3-dioxo-1.3-dihydro-2H-isoindol-2-yl)ethoxy]methyl}-6-methyl-1.4-dihydro-3.5-pyridinedicarboxylate (compound 2c)

92.1 g of methyl2-(o-chlorobenzylidene)-4-(2-phthalimidoethoxy)acetoacetate wasdissolved in 108 ml of 2-propanol at 80° C. 31.3 g ofmethyl-3-aminocrotonate was added and the mixture was heated at the sametemperature for 24 hours. The mixture was evaporated to dryness. Theresidue was dissolved in 162 ml of glacial acetic acid at 80° C. Themixture was cooled to 15C and stirred at the same temperature for 20hours. The solid was filtered off and washed with 83 ml of glacialacetic acid. The solid was suspended in 68 ml of methanol and agitatedfor 30 minutes. The solid was filtered off, washed with 23 ml ofmethanol and dried. The product was recrystallized from ethyl acetate.

Yield: 77.7 g; 69%; purity (HPLC, IN)-96.8%; m.p. 197.5-199° C.

EXAMPLE 6 Diethyl4-(2-chlorophenyl)-2-{[2-(1.3-dioxo-1.3-dihydro-2H-isoindol-2-yl)ethoxy]methyl}-6-methyl-1.4-dihydro-3.5-pyridinedicarboxylate (compound 2b)

116.7 g of ethyl2-(o-chlorobenzylidene)-4-(2-phthalimidoethoxy)acetoacetate wasdissolved in 120 ml of 2-propanol at 80° C. 31.2 g ofethyl-3-aminocrotonate was added and the mixture was heated at the sametemperature for 16 hours. The mixture was evaporated to dryness. Theresidue was dissolved in 180 ml of glacial acetic acid at 80° C. Themixture was cooled to 15° C. and stirred at the same temperature for 20hours. The solid was filtered off and washed with 92 ml of glacialacetic acid. The solid was dissolved in 75 ml of ethanol at 80° C. Thesolution was cooled to 20° C. and the suspension was agitated for 2 h.The solid was filtered off, washed with 25 ml of ethanol. The wetproduct was recrystallized from 60 ml of ethyl acetate.

Yield: 43.6 g (30%) of the product, purity (HPLC, IN)-98.4%; m.p.142.5-144° C.

EXAMPLE 7 3-Methyl 5-ethyl4-(2-chlorophenyl)-2-{[2-(1.3-dioxo-1.3-dihydro-2H-isoindol-2-yl)ethoxy]methyl}-6-methyl-1.4-dihydro-3.5-pyridinedicarboxylate (compound 2d)

87 g of methyl2-(o-chlorobenzylidene)-4-(2-phthalimidoethoxy)acetoacetate wasdissolved in 102 ml of 2-propanol at 80° C. 33.1 g ofethyl-3-aminocrotonate was added and the mixture was heated at the sametemperature for 16 hours. The mixture was evaporated to dryness. Theresidue was dissolved in 153 ml of glacial acetic acid at 80° C. Themixture was cooled to 15° C. and stirred at the same temperature for 20hours. The solid was filtered off and washed with 78 ml of glacialacetic acid. The solid was suspended in 150 ml of methanol and agitatedat 60° C. for 30 minutes. The solid was cooled to 20° C. and filteredoff, washed with 30 ml of methanol and dried. The product wasrecrystallized from ethyl acetate.

Yield: 80 g; 52%; purity (HPLC, IN)-98.2%; m.p. 158-160° C.

EXAMPLE 8 Synthesis of Dimethylamlodipine (Compound 1c) Maleate

62.48 g of compound 2c) was suspended in 630 ml of 40% solution ofmethylamine in water. Temperature of the mixture was adjusted at 25-26°C. and it was agitated for 24 hours. Then the mixture was extracted with940 ml of toluene. Toluene layer was extracted with 310 ml of water.Toluene was distilled off at max. 60° C. on the water bath. The residuewas dissolved in 70 ml of ethanol and 13.95 g of maleic acid in 270 mlof ethanol was added at ambient temperature. After several minutes ofstirring, the solid started to precipitate. The mixture was stirred for2 h at ambient temperature. The crystals were filtered off and washedwith2×50 ml of ethanol The solid was dried at 25° C. for 1 day.

Yield: 38.56 g (63.4% of theory).

Properties: crystalline compound—m.p. 165-166° C. from EtOH¹H-NMR Spectrum:

The ¹H-NMR spectrum was measured at 303.2 K on a Bruker Avance-400 indeuterated dimethylsulfoxide at 400 MHz. δ Assignment 2.34 (s, 3H,H-14); 3.12 (bdd, 2H, H-9); 3.52, 3.54 (s+s, 3H+3H, H-11, H-13); 3.68(m, 2H, H-8); 4.65 (ABq, 2H, H-7); 5.34 (s, 1H, H-4); 6.08 (s, 2H,H-2″); 7.14 (m, 1H, H-4′); 7.24 (bdt, 1H, H-5′); 7.29 (dd, 1H,J_(3′,5′)=1.3Hz, J_(3′,4′)=7.8Hz, H-3′); 7.35 (dd, 1H, J_(4′,6′)=1.8Hz,J_(5′,6′)=7.8Hz, H-6′); 7.89 (bs, ˜3H+ 8.45 s, 1H, NH+HN₂+OH).¹³C-NMR Spectrum:

The ¹³C-NMR spectrum was measured at 303.2 K on a Bruker Avance-400 indeuterated dimethylsulfoxide at 100.6 MHz. δ Assignment  18.16 (C-14); 36.62 (C-4);  38.54 (C-9); 50.42, 50.65 (C-11, C-13);  66.51 (C-7,C-8); 102.00, 102.03 (C-3, C-5); 127.36 (C-5′); 127.71 (C-4′); 128.95(C-3′); 130.74 (C-6′); 131.08 (C-2′); 135.84 (C-2″); 144.39 (C-2);145.18 (C-6); 145.62 (C-1′); 166.63 (C-10); 167.00 (C-12); 167.24(C-1″).

EXAMPLE 9 Synthesis of Diethylamlodipine (Compound 1b) Maleate

The compound was synthesized according to the same procedure as inExample 8, but starting from crystalline compound 2b) (purity—98.4%).

Yield: 22.89 g (93.7% of theory)

Properties: crystalline compound—m.p. 179-180° C. from EtOH.¹H-NMR Spectrum:

The ¹H-NMR spectrum was measured at 303.2 K on a Bruker Avance-400 indeuterated dimethylsulfoxide at 400 MHz. δ Assignment 1.12 (t, J=7.0Hz+1.13 t, J=7.0Hz, sum 6H, H-12+H-15); 2.33 (s, 3H, H-16); 3.11 (dd, ˜2H,J=4.3Hz, J=5.8Hz, H-9); 3.68 (m, 2H, H-8); 4.00 (m, 4H, H-11+H-14); 4.65(ABq, 2H, H-7); 5.33 (s, 1H, H-4); 6.08 (s, 2H, 2xH-2″); 7.15 (m, 1H,H-4′); 7.24 (dt, 1H, J_(3′,5′)=1.3Hz, J_(5′,6′)=7.8Hz, H-5′); 7.29 (dd,1H, J_(3′,5′)=1.3Hz, J_(3′,4′)=7.8Hz, H-3′); 7.36 (dd, 1H,J_(4′,6′)=1.8Hz, J_(5′,6′)=7.8Hz, H-6′); 7.90 (bs, ˜3H+ 8.38 s, 1H,NH+NH₂+OH).¹³C-NMR Spectrum:

The ¹³C-NMR spectrum was measured at 303.2 K on a Bruker Avance-400 indeuterated dimethylsulfoxide at 100.6 MHz. δ Assignment 13.96, 14.02(C-12, C-15);  18.27 (C-16);  36.87 (C-4);  38.55 (C-9); 59.00, 59.29(C-11, C-14); 66.51, 66.61 (C-7, C-8); 102.07, 102.09 (C-3, C-5); 127.17(C-5′); 127.69 (C-4′); 128.90 (C-3′); 131.09 (C-6′); 131.17 (C-2′);135.97 (2xC-2″); 144.22 (C-2); 144.91 (C-6); 145.46 (C-1′); 166.25,166.60 (C-10, C-13); 167.25 (2xC-1″).

EXAMPLE 10 Synthesis of Ethylmethylamlodipine (Compound 1 d) Maleate

The compound was synthesized according to the same procedure as inExample 8, but starting from crystalline compound 2d) (purity—98.2%) andusing methanol as a solvent for final precipitation.

Yield: 45.23 g (71.4% of theory)

Properties: crystalline compound—m.p. 188-189° C. from MeOH¹H-NMR Spectrum:

The ¹H-NMR spectrum was measured at 303.2 K on a Bruker Avance-400 indeuterated dimethylsulfoxide at 400 MHz. δ Assignment 1.11 (t, 3H,J_(13,14)=7.0Hz, H-14); 2.34 (s, 3H, H-15); 3.11 (bdd, 2H, H-9); 3.54(s, 3H, H-11); 3.68 (bt, 2H, H-8); 3.99 (q, 2H, J_(13,14)=7.0Hz, H-13);4.64 (ABq, 2H, H-7); 5.34 (s, 1H, H-4); 6.08 (s, 2H, H-2″); 7.14 (dt,1H, J_(4′,6′)=1.8Hz, J_(3′,4′)=7.8Hz, H-4′); 7.24 (bdt, 1H, H-5′); 7.29(dd, 1H, J_(3′,5′)=1.3Hz, J_(3′,4′)=7.8Hz, H-3′); 7.36 (dd, 1H,J_(4′,6′)=1.8Hz, J_(5′,6′)=7.6Hz, H-6′); 7.90 (bs, ˜3H+ 8.41 s, 1H,NH+NH₂+OH).¹³C-NMR spectrum:

The ¹³C-NMR spectrum was measured at 303.2 K on a Bruker Avance-400 indeuterated dimethylsulfoxide at 100.6 MHz. δ Assignment  14.02 (C-14); 18.24 (C-15);  36.72 (C-4);  38.54 (C-9);  50.63 (C-11);  58.98 (C-13);66.50, 66.52 (C-7, C-8); 101.96 (C-3); 102.20 (C-5); 127.28 (C-5′);127.70 (C-4′); 128.92 (C-3′); 130.90 (C-6′); 131.12 (C-2′); 135.94(C-2″); 144.26 (C-2); 145.08 (C-6); 145.58 (C-1′); 166.54 (C-12); 166.68(C-10); 167.24 (C-1″).

EXAMPLE 11 3-Ethyl 5-prop-2-yl4-(2-chlorophenyl)-2-{[2-(1.3-dioxo-1.3-dihydro-2H-isoindol-2-yl)ethoxy]methyl}-6-methyl-1.4-dihydro-3.5-pyridinedicarboxylate (compound 2e)

15 g of phthalimidoamlodipine (2a) was suspended in 150 ml of2-propanol. To this suspension was added 0.5 ml of concentrated sulfuricacid and the mixture was heated to reflux and for 72 hours. The mixturewas cooled to room temperature and partially evaporated. 50 ml ofn-heptane was added under stirring. A solid started to form, which wasfiltered off and washed with 25 ml of n-heptane. The obtained solid wasdissolved in ethyl acetate for crystallization, but no crystals wereformed even after addition of n-heptane, oil. The mixture was evaporatedand the residual solid dissolved in 35 ml of 2-propanol at reflux.During cooling a solid started to form.

The solid was filtered off and washed with 10 ml of 2-propanol. Afterdrying at 40° C. under vacuum, 10 g of a yellow solid was obtained.

Purity: 90% (HPLC) of the title compound.¹H-NMR Spectrum:

The ¹H-NMR spectrum was measured at 303.2 K on a Bruker Avance-400 indeuterated chloroform at 400 MHz. δ Assignment 1.04 (d, 3H,J_(14,15)=6.3Hz, H-15); 1.16 (t, J_(11,12)=7.0Hz, H-12) 1.24 (d,J_(14,16)=6.3Hz, H-16); 2.42 (s, 3H, H-17); 3.76 (m, 2H, H-8); 4.02 (m,˜4H, H-11+H-9); 4.66 (ABq, 2H, H-7); 4.97 (septet, 1H,J_(14,15)=J_(14,16)=6.3Hz, H-14); 5.35 (s, 1H, H-4); 7.00 (bdt, 1H,J_(4′,6′)=1.8Hz, J˜7.7Hz, H-4′); 7.08 (dt, 1H,J_(3′,5′)=J_(4′,5′)=1.5Hz, J_(5′,6′)=7.5Hz, H-5′); 7.19 (dd, 1H,J_(3′,5′)=1.5Hz, J_(3′,4′)=7.8Hz, H-3′); 7.31 (bs, NH) 7.35 (dd,J_(4′,6′)=1.8Hz, J_(5′,6′)=7.5Hz, H-6′) (+7.31 sum 2H); 7.76 (m, 2H,H-5″+H-6″); 7.88 (m, 2H, H-4″+H-7″).¹³C-NMR spectrum:

The ¹³C-NMR spectrum was measured at 303.2 K on a Bruker Avance-400 indeuterated chloroform at 100.6 MHz. δ Assignment  14.23 (C-12);  18.94(C-17); 21.54, 21.89 (C-15, C-16);  37.29 (C-4);  37.95 (C-9);  59.57(C-11);  66.83 (C-14);  68.18 (C-7);  68.94 (C-8); 100.63 (C-3); 104.16(C-5); 123.35 (C-4″, C-7″); 126.54 (C-5′); 127.16 (C-4′); 129.10 (C-3′);131.78 (C-6′); 132.00 (C-3a″, C-7a″); 132.34 (C-2′); 134.18 (C-5″,C-6″); 144.10 (C-6); 144.90 (C-2); 145.69 (C-1′); 167.15 (C-13); 167.17(C-10); 168.48 (C-3″, C-8″).

EXAMPLE 12 5-methyl 3-prop-2-yl4-(2-chlorophenyl)-2-{[2-(1.3-dioxo-1.3-dihydro-2H-isoindol-2-yl)ethoxy]methyl}-6-methyl-1.4-dihydro-3.5-pyridinedicarboxylate(compound 2f) Step 1): Isopropyl2-(o-chlorobenzylidene)-4-(2-phthalimidoethoxy)-acetoacetate (Compound3c)

17 g of isopropyl 4-(2-(phthalimido)ethoxy)acetoacetate was dissolved in15 ml of isopropanol, under N2, at room temperature, and 7.5 g of2-chlorobenzaldehyde was added. A solution of 0.25 g of piperidine in 5ml of isopropanol was added slowly in 2 hours. When addition wascomplete, the mixture was heated to 35°-40° C. and kept there for 2hours. 1.5 g of glacial acetic acid was added and the mixture was put at−20° C. The solvent was decanted and the remaining solid dissolved in 10ml of isopropanol and put at −20° C. The solvent was decanted again toyield an oil.

For analytical purposes, 5 g of the remaining oil was purified bychromatography on silica gel using ethyl acetate/n-heptane 1/1 (v:v)mixture as the eluent.

Step 2) Condensation with methyl 3-aminocrotonate

20 g of the oil prepared according to Step 1 was dissolved in 30 ml ofisopropanol and 5.1 g of methyl 3-aminocrotonate was added undernitrogen. The mixture was heated to reflux for 18 hours under stirring.The mixture was cooled to room temperature and evaporated to dryness. 15ml of glacial acetic acid was added. A solid was formed which wasfiltered off and washed with 5 ml of glacial acetic acid. The crudeproduct was recrystallized from 25 ml of ethyl acetate. After drying at50° C. under vacuum, 10.2 g of a slightly yellow solid was obtained. Thesolid was recrystallized from ethyl acetate leaving 9.8 g of a solid.¹H-NMR Spectrum:

The ¹H-NMR spectrum was measured at 303.2 K on a Bruker Avance-400 indeuterated chloroform at 400 MHz. δ Assignment 0.98 (d, 3H,J_(11,12)=6.3Hz, H-12); 1.23 (d, ˜3H, J_(11,13)=6.3Hz, H-13); 2.41 (s,˜3H, H-16); 3.61 (s, ˜3H, H-15); 3.77 (m, ˜2H, H-8); 4.01 (m, ˜2H, H-9);4.69 (ABq, ˜2H, H-7); 5.34 (s, 1H, H-4); 7.01 (m, 1H, H-4′); 7.08 (dt,1H, J_(3′,5′)=1.5Hz, J_(5′,6′)=7.5Hz, H-5′); 7.19 (dd, 1H,J_(3′,5′)=1.5Hz, J_(3′,4′)=7.8Hz, H-3′); 7.33 (bs, NH) + 7.34 (dd,J_(4′,6′)=1.8Hz, J_(5′,6′)=7.5Hz, H-6′) (+7.33 sum ˜2H); 7.76 (m, 2H,H-5″+H-6″); 7.88 (m, 2H, H-4″+H-7″).¹³C-NMR Spectrum:

The ¹³C-NMR spectrum was measured at 303.2 K on a Bruker Avance-400 indeuterated chloroform at 100.6 MHz. δ Assignment  18.89 (C-16); 21.45,21.86 (C-12, C-13);  37.08 (C-4);  37.97 (C-9);  50.61 (C-15);  66.97(C-11);  68.22 (C-7);  68.95 (C-8); 101.33 (C-3); 103.57 (C-5); 123.37(C-4″, C-7″); 126.69 (C-5′); 127.16 (C-4′); 129.06 (C-3′); 131.57(C-6′); 131.99 (C-3a″, C-7a″); 132.26 (C-2′); 134.20 (C-5″, C-6″);144.44 (C-6); 144.89 (C-2); 145.90 (C-1′); 166.65 (C-10); 168.13 (C-14);168.51 (C-3″, C-8″).

The invention having been described, it will be readily apparent tothose skilled in the art that further changes and modifications inactual implementation of the concepts and embodiments described hereincan easily be made or may be learned by practice of the invention,without departing from the spirit and scope of the invention as definedby the following claims.

1. A process for producing amlodipine, which comprises: (a) isolating ina solid state a compound of formula (2a) from a reaction mixture

(b) recrystallizing said compound of formula (2a) from a solvent to forma purified compound of formula (2a); and (c) deprotecting said purifiedcompound of formula (2a) to form amlodipine.
 2. The process according toclaim 1, wherein said recrystallization step (b) achieves a purity of atleast 98%.
 3. The process according to claim 2, wherein saidrecrystallization step (b) achieves a purity of at least 99%.
 4. Theprocess according to claim 3, wherein said recrystallization step (b)achieves a purity of at least 99.5%.
 5. The process according to claim1, wherein said recrystallizing is carried out from a solvent selectedfrom the group consisting of ethyl acetate, methanol, ethanol,isopropanol, and mixtures of two or more thereof.
 6. The processaccording to claim 5, wherein said solvent is ethyl acetate.
 7. Theprocess according to claim 6, wherein said recrystallization step (b)achieves a purity of at least 99%.
 8. The process according to claim 1,wherein said isolating step comprises precipitating said compound offormula (2a) from acetic acid to obtain said compound of formula (2a) insolid state.
 9. The process according to claim 1, which furthercomprises forming said compound of formula (2a) in said reaction mixtureby reacting a compound of formula (3a)

with a compound of formula (B 1)

in a suitable solvent.
 10. The process according to claim 9, whereinsaid suitable solvent is isopropanol.
 11. The process according to claim9, wherein said recrystallization step (b) achieves a purity of at least99%.
 12. The process according to claim 11, wherein said recrystallizingis carried out from a solvent selected from ethyl acetate.
 13. Theprocess according to claim 9, which further comprises forming saidcompound of formula (3a) by reacting an o-chlorobenzaldehyde with acompound of formula (C1):

in an organic solvent to form said compound of formula (3a).
 14. Theprocess according to claim 13, wherein said compound of formula (3a) isrecovered from said organic solvent before being reacted with saidcompound of formula (B1).
 15. The process according to claim 13, whereinsaid solvent is isopropanol.
 16. The process according to claim 1, whichfurther comprises converting said amlodipine into a pharmaceuticallyacceptable salt of amlodipine.
 17. In a process for making amlodipine,or a pharmaceutically acceptable salt thereof, that includes formingphthalimidoamlodipine of formula (2a)

and deprotecting it to form amlodipine of formula (1a)

the improvement for which comprises: purifying saidphthalimidoamlodipine by recrystallization to a purity greater than 98%before said deprotecting step.
 18. The process for making amlodipineaccording to claim 17, wherein said phthalimidoamlodipine has a purityof greater than 99% before being subjected to said deprotecting step.19. A process, which comprises the steps of: (a) assaying a sample froma batch of phthalimidoamlodipine for at least one phthalimidoamlodipineimpurity selected from the group consisting of compounds 2b-2f:

(b) determining whether said at least one phthalimidoamlodipine impurityis contained in said sample below a predetermined limit; and, if belowsaid predetermined limit, (c) subjecting said phthalimidoamlodipinebatch to deprotection to form a batch of amlodipine.
 20. The processaccording to claim 19, which further comprises crystallizing said batchof phthalimidoamlodipine prior to said assaying step.
 21. The processaccording to claim 20, which further comprises converting said batch ofamlodipine to a pharmaceutically acceptable salt of amlodipine; andcombining said pharmaceutically acceptable salt of amlodipine with apharmaceutically acceptable excipient to form pharmaceutical unit dosageforms containing an effective amount of said amlodipine salt.